A diverse array of environmental and occupational chemicals are nephrotoxicants. It is important to study the interaction of these chemicals because humans are generally exposed to more than one chemical at a time. As a model for these interactions, this proposal will study the effects of two environmental chemicals, trichloroethylene (TRI) and inorganic mercury (Hg), that both have the kidneys as a primary target organ. TRI is carcinogenic in both laboratory animals and in humans while Hg is acutely cytotoxic. Both chemicals also interact with glutathione (GSH). The nephrotoxicity and nephrocarcinogenicity of TRI is attributed to its bioactivation by GSH conjugation and subsequent processing to the penultimate toxic metabolite S-(1 ,2-dichlorovinyl)-L-cysteine (DCVC), which is metabolized by the cysteine conjugate beta-lyase or flavin-containing monooxygenase, to form reactive species. In contrast, the role of GSH in the handling and nephrotoxicity of Hg is more complex, with GSH having both a protective and an intoxifying role. This proposal will study the interactions between TRI, its metabolite DCVC, and Hg in confluent primary cultures of human proximal tubular (hPT) cells and rat PT (rPT) cells under identical incubation conditions. Four hypotheses will be tested: 1) Pre-exposure of hPT and rPT cells to low, subtoxic concentrations of Hg enhances the bioactivation of both TRI and DCVC by enhancement of expression and activity of enzymes involved in TRI and/or DCVC metabolism; 2) pre-exposure of hPT and rPT cells to low, subtoxic concentrations of Hg enhances cytotoxicity of both TRI and DCVC as a consequence of increases in TRI and/or DCVC bioactivation; 3) pre-exposure of hPT and rPT cells to low- to moderately-toxic concentrations of TRI or DCVC enhances Hg-induced cytotoxicity by depletion of GSH; 4) modulation of cytotoxicity of one chemical in hPT and rPT cells by pre-exposure to another chemical is associated with changes in expression of cytokines, growth factors, and/or heat shock proteins. Results from these studies will provide information on the mechanism of interaction of two important environmental toxicants in a model of human and rat kidney cells and will allow us to determine factors that contribute to species differences in susceptibility.
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